SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma

Glioblastoma (GBM) relies on fatty acid metabolism for aggressive growth. This study identifies stearoyl-CoA desaturase-5 (SCD5), a brain-enriched isoform, as a critical driver of glioblastoma stem cell (GSC) maintenance and genomic stability. While SCD1's role in GBM is well-established, our research reveals that SCD5 plays a non-redundant role by preferentially desaturating C18:0 and uniquely remodeling sphingolipids. Genetic silencing of SCD5 disrupts the cell cycle, impairs DNA repair, and triggers parthanatos-a form of cell death caused by PARP1 hyperactivation. Mechanistically, loss of SCD activity or saturated fatty acid accumulation triggers PARP1 hyperactivation and subsequent degradation, depleting RAD51 to compromise homologous recombination and induce parthanatos. These findings uncover a lipid-mediated vulnerability in GBM, linking fatty acid desaturation to PARP1-dependent genome integrity. Targeting SCD5 may offer a therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.